Characterizing the clinical features and atrophy patterns of MAPT-related frontotemporal dementia with disease progression modelling (Supplementary Data)

Background and Objective: Mutations in
the MAPT gene cause frontotemporal dementia (FTD). Most
previous studies investigating the neuroanatomical signature
of MAPT mutations have grouped all different mutations
together and shown an association with focal atrophy of the temporal lobe.
However, the variability in atrophy patterns between each
particular MAPT mutation is less well
characterised. We aimed to investigate whether there were
distinct groups of MAPT mutation carriers based on their
neuroanatomical signature. Methods: We applied Subtype and Stage
Inference (SuStaIn), an unsupervised machine learning technique that
identifies groups of individuals with distinct progression patterns, to
characterise patterns of regional atrophy in MAPT-associated FTD
within the Genetic FTD Initiative (GENFI) cohort study. 
Results: 82 MAPT mutation carriers were
analysed, the majority of whom had P301L, IVS10+16 or R406W mutations,
along with 48 healthy non-carriers. SuStaIn identified two groups
of MAPT mutation carriers with distinct atrophy
patterns: a ‘temporal’ subtype in which atrophy was most prominent in the
hippocampus, amygdala, temporal cortex and insula, and a ‘frontotemporal’
subtype in which atrophy was more localised to the lateral temporal lobe
and anterior insula, as well as the orbitofrontal and ventromedial
prefrontal cortex and anterior cingulate. There was a one-to-one mapping
between IVS10+16 and R406W mutations and the temporal subtype, and a near
one-to-one mapping between P301L mutations and the frontotemporal subtype.
There were differences in clinical symptoms and neuropsychological test
scores between subtypes: the temporal subtype was associated with amnestic
symptoms, whereas the frontotemporal subtype was associated with executive
dysfunction.  Discussion: Our results demonstrate that
different MAPT mutations give rise to distinct atrophy
patterns and clinical phenotype, providing insights into the underlying
disease biology, and potential utility for patient stratification in
therapeutic trials.